Triple-negative breast cancer (TNBC) accounts for 15-20% of all diagnosed breast cancers worldwide. TNBC carries a poorer prognosis and lower survival rate compared to other breast cancer subtypes. Identifying novel targets and new therapeutics to treat patients diagnosed with TNBC remains a significant priority of the National Institutes of Health. Product and Long-Term Goal: Nanometics is developing an orally available and targeted therapeutic, dubbed MTDIA for the treatment of TNBC. MTDIA inhibits a novel target, 5 -methylthioadenosine phosphorylase (MTAP), and selectively disrupts the epigenetic development of cancer cells. Technical Innovation: MTAP is the sole enzyme responsible for metabolizing 5 -methylthioadenosine (MTA) in humans, which facilitates recycling of S-adenosylmethionine (AdoMet). MTAP is a promising target for cancer therapeutics because it is linked to various anticancer pathways. MTDIA is a powerful transition state inhibitor of MTAP (Ki* = 86 pM), and a single oral dose causes systemic MTAP inhibition and a disruption in MTA / AdoMet homeostasis that impairs the epigenetic development of cancer cells. Phase I SBIR Equivalent Outcomes: Once-daily oral doses of MTDIA are effective against eight cell line derived xenograft (CDX) models of six different human cancers. Once-daily dosing with MTDIA inhibits MTAP for >24 h, causes whole-body increases in MTA levels (up to 100-fold in plasma), suppresses the growth rate of TNBC primary tumors and causes dramatic regression of large TNBC tumors. Escalating dose studies in mice demonstrate a lack of observable toxicity for MTDIA up to 1,000 mg/kg/day for 7 days. Pharmacokinetic, pharmacodynamic, and genomic analyses provide strong evidence for the MTDIA mechanism of action. Direct Phase II Objectives: Demonstrate that: (1) oral doses of MTDIA are effective in patient derived xenograft (PDX) models of TNBC; and (2) optimize the multi-kilogram synthesis of MTDIA phosphate. Expected Outcomes: Demonstration of efficacy in PDX models and optimization of the multi-kilogram synthesis is expected to de-risk the program for human clinical trials. Commercial Application: The global market for breast cancer therapeutics is forecast to reach $13.86 billion by 2017. Because the treatment options for metastatic relapse of TNBC are limited, there remains a significant need for new drugs that work through novel modes of action.